Adding Protein Context to the Human Protein-Protein Interaction Network to Reveal Meaningful Interactions
Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimer's disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways. Protein-protein-interactions (PPIs) participate in virtually all biological processes. However, the PPI map is not static but the pairs of proteins that interact depends on the type of cell, the subcellular localization and modifications of the participating proteins, among many other factors. Therefore, it is important to understand the specific conditions under which a PPI happens. Unfortunately, experimental methods often do not provide this information or, even worse, measure PPIs under artificial conditions not found in biological systems. We developed a method to infer this missing information from properties of the interacting proteins, such as in which cell types the proteins are found, which functions they fulfill and whether they are known to play a role in disease. We show that PPIs for which we can infer conditions under which they happen have a higher experimental reliability. Also, our inference agrees well with known pathways and disease proteins. Since diseases usually affect specific cell types, we study PPI networks of influenza proteins in lung tissues and of Alzheimer's disease proteins in neural tissues. In both cases, we can highlight interesting interactions potentially playing a role in disease progression.